Obesity is the most prevalent nutritional disorder in Western societies. More than three in ten adult Americans weigh at least 20% in excess of their ideal body weight. Increased body weight is an important public health problem because it is associated with type II diabetes, hypertension and hyperlipidemia. Moreover, adults tend to gain weight, as they get older. Our data suggests that the F-344/BN rat is a reasonable model for age-related obesity in humans. These rats demonstrate a steady increase in body fat into early senescence similar to what occurs in humans. Most obese animal models, whether associated with genetic, diet-induced or age-related obesity, display pronounced leptin resistance, rendering leptin treatment futile in treating obesity. We discovered that aged rats display central leptin resistance characterized by reduced hypothalamic leptin receptors and diminished STAT3 signaling, and that elevated central leptin due to recombinant adeno-associated virus (rAAV) leptin gene delivery induces a leptin resistance in rats of various ages. Elevated central leptin and reduced leptin receptor expression/numbers appear to be common to all models of leptin resistance. Our central hypothesis focuses on two aspects of the leptin signal cascade: (1) diminished leptin signaling associated with elevated central leptin, in particular reduced activity of the leptin-activated insulin receptor substrate (IRS)-mediated phosphatidylinositol-3-OH kinase (PI3K) pathway constitutes one component of age-related or leptin-induced leptin resistance; and (2) elevated central leptin with age contributes to diminished leptin signaling and leptin resistance independent of obesity. We will test our hypotheses by examining (1) whether the leptin activated IRS-PI3K signaling pathway is impaired with age and with leptin-induced leptin resistance; (2) whether inhibition of the IRS-PI3K component of leptin signaling facilitates the development of leptin resistance; and if elevated central leptin with age is the primary factor in impaired leptin signaling and leptin resistance independent of obesity. Understanding the nature of the leptin resistance is paramount to combating obesity, for only then can we fully exploit the potency of leptin in otherwise leptin-resistant rodents or humans. Such discoveries may lead to new treatments for obesity and the diabetes associated with obesity.